p19Arf, HMGA2 and MDM2 For Use in the Diagnosis and Treatment of Aberrant Cell Growth

a technology hmga2, which is applied in the field of p19arf, hmga2 and mdm2 for use in the diagnosis and treatment of aberrant cell growth, can solve the problems of limited treatment options besides surgical removal by hysterectomy or tumor enucleation, and the challenge of permanent shrinkage of fibroids, so as to confirm the induction of senescence and apoptosis, confirm the over

Inactive Publication Date: 2013-06-13
UNIV OF BREMEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0012]In a second series of experiments additional tissue samples from UL (see Table 1 in FIG. 20) were investigated confirming an overexpression of Arf in uterine leiomyomas compared to myometrial tissue. Further antagonists and inhibitors of the expression, respective oncogenic activity of the protein MDM2 were tested as well, confirming the induction of senescence and apoptosis in the UL-cells and the general usefulness of MDM2 antagonists, on the basis of their common mode of action in the therapy of UL. Furthermore, in addition to cells and tissue from uterine leiomyomas, cells from another tissue of mesenchymal origin, i.e. adipose-tissue derived stem cells (ADSCs) were treated with an MDM2-inhibitor. Comparable to the effect on UL cells, said treatment led to an decreased self-renewal capacity of these cells as well, pointing at a general usefulness of the methods and compounds of the present invention in the treatment of diseases characterized by an aberrant growth of mesenchymal stem cells and their descendants, wherein the diseases are selected from the group comprising endometriosis, adenomyosis, endometrial hyperplasia, leiomyoma, lipoma, hamartoma of the lung, fibroadenoma of the breast, adenoma of the salivary gland, and aggressive angiomyxomas. Accordingly, obesity, as a disorder characterized by an overgrowth of the adipose tissue may be treated according to the methods of the present invention as well.

Problems solved by technology

Despite their high prevalence the treatment options besides surgical removal by hysterectomy or tumor enucleation are still limited.
Thus, therapies aimed at permanent shrinkage of the fibroids still remain a challenge.

Method used

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  • p19Arf, HMGA2 and MDM2 For Use in the Diagnosis and Treatment of Aberrant Cell Growth
  • p19Arf, HMGA2 and MDM2 For Use in the Diagnosis and Treatment of Aberrant Cell Growth
  • p19Arf, HMGA2 and MDM2 For Use in the Diagnosis and Treatment of Aberrant Cell Growth

Examples

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example 1

In Vitro Senescence Accompanied by a Decrease of the Expression of HMGA2 and an Increase of p19Arf

[0099]22 uterine leiomyomas and seven myometrial tissues have been tested by qRT-PCR for their relative expression of p16Ink4a and p19Arf mRNA. Based on cytogenetic analyses, the leiomyomas were further divided into a group with 12q14˜15 aberrations (n=10) and another group with other karyotypes (n=12). While in the control (adipose tissue derived stromal cells, ADSCs, 6th in vitro passage) but in none of the samples an expression of p16Ink4a mRNA was detectable, p19Arf mRNA was detectable in all samples measured and was found in the range detected in ADSCs (FIG. 1). Generally, the expression of p19Arf in leiomyomas varied over a broad range while it was almost identical in the myometrial tissue. The relative p19Arf mRNA expression in the leiomyomas significantly (pArf mRNA-level of 0.062 (range: 0.009-0.104) in myometrial tissue and of 0.704 (range: 0.034-3.675) in uterine leiomyomas b...

example 2

Antagonizing MDM2 Induces Senescence as Well as Apoptosis in Fibroid Cells In Vitro

[0100]These findings obtained in accordance with the present invention suggest that in vitro senescence of leiomyoma cells is controlled by the HMGA2-p19Arf axis. Thus, a similar mechanism seems to account for the in vivo aging of stem cell populations as well as for in vitro senescence of cells from uterine fibroids. Thus, it is tempting to assume that in vivo senescence contributes to the growth control of UL as well. There are some recent data supporting this idea. It was demonstrated, e.g., that uterine leiomyomas express significantly higher levels of p19Arf than myometrial tissue and that in leiomyomas delicate balances along the HMGA2-p19Arf-MDM2-p53-p21 axis seem to exist that dictate the fate of the individual fibroids. Because of the possible similarities between in vitro and in vivo senescence of these tumors it was addressed next whether in vitro this balance can be disturbed by MDM2 inhib...

example 3

p19Arf Drives Senescence as Well as Apoptosis in Uterine Fibroids

[0102]Because data showed that inhibition of MDM2 triggers the senescence pathway as well as apoptosis the inventors were interested whether p19Arf / MDM2 may also correlate with the expression of an apoptosis marker, i.e. BAX in vivo. Thus, samples from a total of 29 UL of both most frequent karyotypic groups were analyzed for possible correlations between p19Arf and BAX and p21 and BAX. Interestingly, a highly significant correlation was found in both analyses (FIG. 7, 8) suggesting that in vivo p19Arf does not only induce senescence but simultaneously part of the tumor cell population becomes committed to apoptosis with both clearly depending on the level of p19Arf. This latter finding is confirmed by a highly significant correlation between the expression of p21 and BAX.

[0103]Discussion

[0104]Uterine fibroids are highly common benign tumors of women in their reproductive age. In numerous studies, the influence of the ...

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Abstract

Provided are novel methods and compositions for the diagnosis, prognosis and treatment of leiomyomas, in particular uterine leiomyoma (UL). In addition, methods of identifying anti-tumor agents are described. Furthermore, novel methods and compositions are provided for the treatment of diseases characterized by an aberrant growth of mesenchymal stem cells and their descendants and for the treatment of obesity are disclosed.

Description

FIELD OF THE INVENTION[0001]The present invention is generally concerned with the expression, detection of gene products and modulation of activity of the genes p19Arf, HMGA2 and MDM2 for use in the diagnosis of diseases associated with aberrant cell growth and with the provision of novel means in treatment of said diseases. In a first aspect the present invention relates to a method of diagnosing whether a subject has, or is at risk for developing leiomyomas, in particular uterine leiomyoma (UL) comprising measuring the level of p19Arf and HMGA2 in a test sample derived from a UL, wherein increased levels of p19Arf and / or MDM2 and / or their gene transcripts, respectively, and an increased level of HMGA2 and / or its gene transcript, respectively, in the test sample relative to the level of levels compared to a control sample is indicative of a rapidly growing leiomyoma that is sensitive. Furthermore, a novel therapy of UL is provided by use of an MDM2 inhibitor for use in the treatmen...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K31/496A61K31/17A61K31/7052A61K31/381C12Q1/68A61K38/18
CPCA61K31/00C12Q1/686A61K31/381A61K31/496A61K31/713A61K38/18G01N33/57442A61K45/06C12N15/1135C12N2310/14A61K31/17A61K31/7052A61K38/1825A61K38/1841A61K38/1858A61K38/1875A61K39/3955A61K31/167A61P3/04A61P5/00A61P15/00
Inventor BULLERDIEK, JORNMARKOWSKI, DOMINIQUE N.
Owner UNIV OF BREMEN
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